Q U I N T E S S E N C E I N T E R N AT I O N A L
PERIODONTOLOGY
Efficacy of forced eruption/enamel matrix derivative
with freeze-dried bone allograft or with demineralized
freeze-dried bone allograft in infrabony defects:
A randomized trial
Shigeki Ogihara, DDS, PhD1/Dennis P. Tarnow, DDS2
Objective: To determine the efficacy of enamel matrix deriva-
tive (EMD) and forced eruption alone or in combination with
freeze-dried bone allograft (FDBA) or demineralized FDBA
(DFDBA) when managing infrabony defects. Method and
Materials: Seventy-four patients with an inadequate biologic
width due to subgingival caries were randomly assigned to
one of three intervention groups: Ortho/EMD/FDBA (OEF)
(n = 25), Ortho/EMD/DFDBA (OED) (n = 24), and Ortho/EMD
alone without graft material as a control (OE) (n = 25). Each
patient donated an infrabony defect. The primary outcomes
were absolute change in probing depth (PD) reduction and
clinical attachment level (CAL) gain from baseline to 1- and
3-year follow-up. Infrabony defects were surgically treated
with EMD/FDBA, EMD/DFDBA, or EMD alone 4 weeks before
orthodontic extrusive force was applied to reestablish a bio-
Key words: bone, clinical trial, enamel matrix protein, forced eruption, randomized, tissue regeneration
The function of the periodontal ligament (PDL) has
been studied extensively.1,2 Its healing potential
depends on the PDL fibers being intact and function-
ing, and new bone formation is associated with a new
functioning PDL fiber on the tension side.1-3 Therefore,
this poses a limitation to classic orthodontics in treating
1 Private Practice, Tokyo, Japan.
2 Clinical Professor, Department of Periodontology, Columbia University College
of Dental Medicine, New York, NY, USA.
Correspondence: Dr Shigeki Ogihara, 23-5 Adachi 4 chome, Adachi-ku,
Tokyo, 1200015, Japan. Email: oshigeki@spn1.speednet.ne.jp
VOLUME 46 • NUMBER 6 • JUNE 2015
Shigeki Ogihara
logic width of 2 mm. Results: Seventy-four patients (OEF,
n = 25; OED, n = 24; OE, n = 25) were analyzed. All groups
demonstrated significant improvement in PD reduction and
CAL gain from baseline. The changes at 1 year for PD were: OEF
(mm, 95% CI), 4.3, 3.7 to 4.7; OED, 4.2, 3.6 to 4.9; and OE, 3.4,
3.1 to 3.7; for CAL, changes were: OEF, 4.3, 3.9 to 4.7; OED, 3.9,
3.5 to 4.4; and OE, 3.3, 3.1 to 3.5. Longer follow-ups showed
similar findings. Conclusion: This study showed that both
forced eruption/EMD/FDBA and forced eruption/EMD/DFDBA
combination therapies result in greater soft tissue improve-
ments at 1- and 3-year follow-up in addition to greater hard
tissue improvements at 6-month re-entry compared with
forced eruption/EMD alone. (Quintessence Int 2015;46:481–490;
doi: 10.3290/j.qi.a33936)
advanced interdisciplinary cases that lack intact func-
tioning PDL fibers as a result of severe periodontal
destruction.
Juzanx and Giovannoli4 established the new guide-
line for the use of enamel matrix derivative (EMD) to
alter the pre-orthodontic periodontal condition,
obtaining a new functioning PDL fiber in a case series.
This guideline supported the use of EMD alone, without
membrane, to prevent long junctional epithelium
down growth,4,5 whereas other research failed to sup-
port the use of EMD alone for orthodontic regenerative
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combination therapy because of insufficient data.5-7
Thus, the use of EMD as a monotherapy may be limited.
Our previous randomized controlled trial (RCT)
established that allograft materials (freeze-dried bone
allograft [FDBA] and demineralized FDBA [DFDBA])
were successful in managing deep infrabony defects
when combined with EMD.8 Furthermore, the efficacy
of forced eruption combined with EMD/DFDBA has
been demonstrated for the correction of 2- and 3-wall
infrabony defects in another RCT.9 However, it is less
clear whether this same efficacy of EMD/FDBA or EMD/
DFDBA may be beneficial over EMD alone with forced
eruption. Therefore the aim of this study was to deter-
mine the efficacy of forced eruption with EMD/FDBA
versus forced eruption with EMD/DFDBA versus forced
eruption with EMD alone in treating infrabony peri-
odontal defects. It was hypothesized that both FDBA/
EMD and DFDBA/EMD are not more effective than EMD
alone when combined with forced eruption in soft and
hard tissue improvement in infrabony defects.
METHOD AND MATERIALS
The study protocol was approved by the institutional
review board at the Tokyo Adachi Dental Society
(Tokyo, Japan), and performed in accordance with the
Helsinki Declaration of 1975, as revised in 2000. The
trial was registered at the Japan Medical Association
Center for Clinical Trials (JMACCT CTR), which is a mem-
ber of the World Health Organization international clin-
ical trials registry, number JMA-IIA00077. Prior to
obtaining written informed consent, the patients were
informed about the nature of the study and the pro-
cedures involved, as well as potential risks and benefits
associated with the therapy received.
A randomized, parallel clinical trial was conducted
in a private periodontal practice (SO) in Tokyo between
April 2004 and October 2011. Patients were recruited
from this private practice. The recruited patients had
chronic periodontitis (CP) with an inadequate biologic
width due to subgingival caries, and required peri-
odontal treatment. Complete medical and dental histo-
ries were obtained along with comprehensive clinical
482
and radiographic examinations. The exclusion criteria
included the following:
• systemic diseases influencing periodontal surgery
• systemic medications affecting periodontal status
• pregnancy or lactation
• smoking
• sensitivity to minocycline and tetracycline.
Patients with a clinical attachment level (CAL) ≥ 6 mm,
associated with radiographic bone loss, were eligible if
they had completed the initial phase of therapy. This
included full-mouth scaling, root planing, and occlusal
adjustment where indicated, as well as oral hygiene
instructions 2 months before enrollment. Each patient
donated no more than one infrabony defect. Following
the completion of baseline measurements, 74 partici-
pants were randomly assigned by a computer gener-
ated list of random numbers into one of three treat-
ment groups (Fig 1):
• Ortho/EMD/FDBA (OEF): n = 25; 6 men and 19
women; mean age (years) ± SD = 52 ± 9
• Ortho/EMD/DFDBA (OED): n = 24; 4 men and 20
women; mean age ± SD = 51 ± 11
• Ortho/EMD alone without graft material (OE) as a
control: n = 25; 6 men and 19 women; mean
age ± SD = 50 ± 5.
The participants were observed from baseline to 3
years of follow-up for outcome measurements. One
examiner (SO) measured the PD and CAL with a cali-
brated periodontal probe (Williams probe, Hu-Friedy) at
baseline to 1- and 3-years’ follow-up. The PD was the
greatest distance from the gingival margin to the base
of the pocket, whereas CAL was the corresponding
distance from the cementoenamel junction (CEJ),
crown, or restoration margin to the base of the pocket.
The primary outcome measures were the absolute
change in mean PD reduction and CAL gain from base-
line to 1 and 3 years postoperative. The secondary
outcome measure was absolute change in the mean
open probing attachment level (OPAL) gain from base-
line to 6 months re-entry to evaluate additional effects
of the interventions (ie, the hard tissue improvement).
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Assessed for eligibility (n=74)

Enrollment Excluded (n= 0)

Randomized (n=74)

Ortho/EMD/FDBA (n=25) Ortho/EMD (control) (n=25) Ortho/EMD/DFDBA (n=24)

Allocation Received Ortho/EMD/
FDBA (n=25)
Received Ortho/
EMD (n=25)
Received Ortho/EMD/
DFDBA (n=24)

None lost to follow-up at None lost to follow-up at None lost to follow-up at

Follow-Up 1 year (n=25) 1 year (n=25) 1 year (n=24)

Analyzed at 1 year (n=25) Analyzed at 1 year (n=25) Analyzed at 1 year (n=24)

Analysis
Analyzed at 3 years (n=25) Analyzed at 3 years (n=25) Analyzed at 3 years (n=24)

Fig 1 Flow diagram of the study.

OPAL was the greatest distance from CEJ, crown, or res-
toration margin to the base of the defect. Additionally,
recordings were made for plaque index (PI)10 and
bleeding on probing (BOP) from baseline to 1 and 3
years postoperative.
Procedure
Immediately prior to surgery, all patients rinsed with a
0.12% chlorhexidine solution (Hibitane, Sumitomo Dai-
nippon Pharma) for 30 seconds. After topical and local
anesthesia (2% xylocaine for dental use; Dentsply
Sankin), sulcular incisions were made before a full thick-
ness flap was reflected. The infrabony defects were
completely debrided, root planed with hand instru-
ments (Gracey curette, Hu-Friedy) and a piezo-electric
ultrasonic generator (Piezotome, Satelec Acteon), and
then categorized according to their morphology
(Table 1). The same examiner (SO) measured the OPAL.
Minocycline solution (10 mg/mL; Minomycine 50,
Pfizer) has anti-collagenase and antibacterial activity11
and was used as a root-conditioning agent for 3 min-
utes. The surgical site was well isolated and thoroughly
irrigated with sterile water before EMD (Emdogain,
Straumann) was applied. A composite graft consisting
of FDBA (250 to 1000 μm) or DFDBA (250 to 710 μm)
(Oragraft, LifeNet Health) obtained from the same tis-
sue bank, was mixed with minocycline solution (10 mg/
mL) (0.5 mL FDBA/DFDBA containing 0.1 mL minocy-
cline solution; Minomycine 50)12 and EMD (0.5 mL
FDBA/DFDBA containing 0.3 mL of EMD), and placed

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Table 1 Baseline demographic and clinical characteristics of 74 patients undergoing Ortho/EMD/FDBA, Ortho/
EMD/DFDBA and Ortho/EMD (control)

Characteristic Ortho/EMD/FDBA (n = 25) Ortho/EMD/DFDBA (n = 24) Ortho/EMD (control) (n = 25)

Age, mean (SD), y 52 (9) 51 (11) 50 (5)
Female, n (%) 19 (76) 20 (83) 19 (76)
Male, n (%) 6 (24) 4 (17) 6 (24)
1-walled 0 (0) 0 (0) 0 (0)
Defect 2-walled 10 (40) 9 (37) 10 (40)
morphology,
n (%) 3-walled 13 (52) 11 (46) 13 (52)
Combination 2 (8) 4 (17) 2 (8)
Incisor 4 (16) 5 (21) 4 (16)

Tooth, Canine 1 (4) 1 (4) 0 (0)

n (%) Premolar 9 (36) 8 (33) 9 (36)
Molar 11 (44) 10 (42) 12 (48)

Location, Maxilla 16 (64) 14 (58) 16 (64)

n (%) Mandible 9 (36) 10 (42) 9 (36)
PD, mean (SD), mm 6.52 (0.91) 6.75 (1.29) 6.56 (0.58)
CAL, mean (SD), mm 7.28 (0.79) 7.29 (1.19) 7.28 (0.68)
CEJ-BD, mean (SD), mm 7.96 (2.60) 7.67 (1.90) 7.44 (0.58)
PI, mean (SD) 0.17 (0.003) 0.18 (0.03) 0.18 (0.02)
BOP, mean (SD) 18 (3.3) 19 (3.6) 18 (2.8)

into the infrabony defect to fill or slightly overfill the
lesion. Flaps were reapproximated and sutured to
achieve a tension-free primary closure. Horizontal mat-
tress and single interrupted sutures using a 5-0 mono-
filament suture (Ethicon, Johnson & Johnson) were
placed to ensure flap adaptation and closure. The
remaining EMD was gently applied to the flap margins
to enhance soft tissue wound healing. The patients
were instructed to avoid brushing and flossing at the
surgical site until the sutures were removed 7 days
post-surgery, and they were prescribed Minocycline
(Minomycine 50) at 100 mg per day for 4 days.
The teeth had extensive subgingival caries requiring
endodontic treatment and forced eruption to establish
2 mm biologic width before crown placement. An elas-
tic hook (stainless steel wire, Dentsply Sankin) was
placed into the root canal of the target teeth by direct
bonding for forced eruption before performing peri-
odontal regenerative surgery. At 4 weeks post-surgery,
forced eruption was initiated to enhance angiogenesis
along with tooth movement.9 This time frame allowed
for soft tissue healing, especially in the interproximal
area where re-epithelialization was observed in the
majority of the treated cases. Just prior to initiating
active orthodontic treatment, an occlusal metal bar (a
fixed orthodontic appliance) was bonded to the adja-
cent teeth, with or without orthodontic mini-implant
anchorage to enable orthodontic forced eruption of
the target tooth. To prevent root resorption, a light
orthodontic force was used to interrupt movement
(15 g for anterior teeth to 50 g for posterior teeth).13
This force, with a rate of extrusion of no more than
2 mm per month, was directed occlusally within an
alveolar housing for 4 weeks. Elastics (FM Super Thread
T-045, Morita) were changed every 5 days to provide a
constant force on the target tooth. Temporary stabiliza-
tion with ligature and resin (Unifast II, GC) was provided
4 weeks post forced eruption. The patients were
observed weekly for the first month, and then monthly
for up to 6 months for postoperative treatment, which

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a b c d e f
Figs 2a to 2f Ortho/EMD/DFDBA in the treatment of an infrabony defect. (a) Baseline radiograph. (b) Extent of the infrabony defect
demonstrated by the insertion of a periodontal probe. (c) Initial forced eruption. (d) Completed forced eruption followed by temporary
stabilization. (e) Re-entry 6 months after initial surgery confirmed complete filling of the infrabony defect. (f) Radiograph at 3-year follow-up.

a b c d e f
Figs 3a to 3f Ortho/EMD/FDBA in the treatment of an infrabony defect. (a) Baseline radiograph. (b) Extent of the infrabony defect.
(c) Initial forced eruption. (d) Completed forced eruption followed by temporary stabilization. (e) Re-entry 6 months after initial surgery
confirmed complete filling of the infrabony defect. (f) Radiograph at 1-year follow-up.

included plaque debridement, topical use of an oral
rinse with 0.12 % chlorhexidine solution (Hibitane) and
reinforcement of oral hygiene. Six months after the
initial surgery, a re-entry procedure was performed and
OPAL was measured. The target teeth were restored
after the surgical sites were healed. Primary outcomes
included the absolute change in the mean PD reduc-
tion and CAL gain from baseline to 1- and 3- years fol-
low-up. Following the treatment period, the patients
were observed at least every 6 months for up to 3 years
(Figs 2 and 3).
Radiographic measurements
Periapical radiographs (Kodak Ultraspeed film, size 2
DF-58; Kodak), at baseline and 1 and 3 years postopera-
tive, were taken with the parallel technique using film
holders (Dentsply Rinn). The radiographs were digitized
(Kodak photo DVD, 6,000,000 dpi; Kodak) and mea-
sured with an electronic ruler (Image J; NIH) on a high
definition monitor (HP ZR24w, served with a NVIDIA
Quadro graphic board; Hewlett Packard) at a resolution
of 1,920 × 1,200 pixels.14 Radiographic bone gain, which
was the corresponding distance from CEJ to the bot-
tom of the bony defect (BD), was chosen as a radio-
graphic outcome variable for OPAL. The differences
between baseline and 1- and 3-year radiographic bone
gain were measured by one examiner (SO).
Statistical method
The allocation schedule was created as the source of a
computer-generated list of random numbers and was
concealed from investigators by SO alone. The patients
were enrolled and assigned to groups. A sample size of
20 patients per group was necessary to detect mean
differences of clinical parameters with a two-tailed 5%
significance level and a power of 97%, given an antici-
pated dropout rate of 10%; therefore, the sample size
(25, 24, 25) for this study was adequate. Data were ana-
lyzed using an intention-to-treat and per-protocol prin-
ciple. Confidence intervals (CIs) of 95% are reported for

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within group changes and between group differences
at all end points. Analysis of covariance indicated a
statistically significant difference between the groups
in the PD, CAL, and OPAL. Further analysis was per-
formed using Tukey’s test for multiple comparison. The
Wilcoxon signed-ranked test was used to determine
the differences in within-group changes in PD, CAL,
OPAL, PI, BOP, and radiographic bone gain; all tests
were two-tailed with a significance level of 5%. To inter-
pret negative study results (P ≥ .05), a post hoc power
analysis was performed using the mean difference and
standard deviation (SD). Statistical software (XLSTAT-
Pro, Addinsoft) and spreadsheet software (Office 2010,
Microsoft) were used in data analysis.
RESULTS
Clinical and demographic results
From April 2004 to October 2011, 74 patients diag-
nosed with CP having an inadequate biologic width
were recruited from a periodontal private practice. The
OEF group (n = 25), OED group (n = 24), and OE (con-
trol) group (n = 25) had similar demographic and base-
line characteristics (Table 1). The flow diagram in Fig 1
shows the recruitment, inclusion, assignment, and sub-
sequent follow-up of the study patients.
Primary outcome parameter
All groups demonstrated significant improvement in
PD reduction and CAL gain compared to the baseline.
The changes at 1 year for PD were: OEF (mm, 95% CI),
4.3, 3.7 to 4.7; OED, 4.2, 3.6 to 4.9; and OE, 3.4, 3.1 to 3.7;
for CAL, changes were: OEF, 4.3, 3.9 to 4.7; OED, 3.9, 3.5
to 4.4; and OE, 3.3, 3.1 to 3.5. Longer follow-ups showed
similar findings (Table 2). Between 1 and 3 years, none
of the groups showed statistically significant differ-
ences in PD reduction or CAL gain (Table 2). The inter-
vention groups showed better treatment outcomes
than the control group at 1 and 3 years postoperative.
There were statistically significant differences as well as
clinical differences in PD reduction and CAL gain
between the OEF and control groups at 1 and 3 years
postoperative. In contrast, there were statistically sig-
486
nificant differences in PD reduction and CAL gain
between the OED and the control groups at 1 and 3
years postoperative (Table 3). There were no statisti-
cally significant differences in PD reduction or CAL gain
between the OEF and the OED groups at 1 and 3 years
postoperative (Table 3).
Secondary outcome parameter
All groups demonstrated significant improvement in
OPAL gain compared to the baseline (Table 2). There
were statistically significant differences as well as clin-
ical differences in OPAL gain between the two interven-
tion groups and the control group at 6-month re-entry
(Table 3). There was no statistically significant differ-
ence in OPAL gain between the OED and OEF groups at
6-month re-entry (Table 3).
There were no adverse outcomes, such as allergic
reactions to either EMD or the graft materials or root
resorption, to report from any of the treatment groups.
Radiographic outcome parameter
All groups demonstrated significant improvement in
radiographic bone gain compared to the baseline.
Between 1 and 3 years postoperative, none of the
groups showed statistically significant differences
(Table 2). There were statistically significant differences
as well as clinical differences in radiographic bone gain
among both intervention groups and the control group
at 1 and 3 years postoperative (Table 3). There was no
statistically significant difference in radiographic bone
gain between the OED and OEF groups at 1 and 3 years
postoperative (Table 3).
DISCUSSION
Overall, the current trial indicated that both graft ma-
terials were successful in managing deep infrabony
defects when combined with Ortho/EMD. Both Ortho/
EMD/FDBA and Ortho/EMD/DFDBA interventions
resulted in significantly higher soft tissue improvement
at 1- and 3-year follow-ups in addition to significantly
higher hard tissue improvement at 6-month re-entry
compared to the Ortho/EMD control. The hypothesis,
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Table 2 Comparison of PD, CAL, radiographic bone gain (CEJ–bony defect), PI, BOP, and OPAL (mean [SD]) at
baseline and 1- and 3-year follow-ups (within group changes)

Baseline to 1 year 1 year to 3 years Baseline to 3 years

Difference Difference Difference
Parameter Treatment Baseline 1 year (95% CI) P 3 years (95% CI) P (95% CI) P
Ortho/EMD/FDBA 6.52 2.20 4.32 2.24 0.04 4.28
< .0001 .74 < .0001
(n = 25) (0.91) (0.41) (3.70 to 4.67) (0.44) (−0.28 to 2.00) (3.91 to 4.65)
Ortho/EMD/DFDBA 6.75 2.54 4.21 2.58 0.09 4.17
PD < .0001 .78 < .0001
(n = 24) (1.29) (0.50) (3.55 to 4.87) (0.50) (−0.32 to 0.24) (3.48 to 4.76)
(mm)
Ortho/EMD
6.56 3.20 3.36 3.28 0.08 3.28
(negative control) < .0001 .63 < .0001
(0.58) (0.64) (3.05 to 3.67) (0.54) (−0.41 to 0.25) (2.98 to 3.59)
(n = 25)
Ortho/EMD/FDBA 7.28 3.00 4.28 3.08 0.08 4.20
< .0001 .50 < .0001
(n = 25) (0.79) (0.36) (3.91 to 4.65) (0.40) (−0.29 to 0.13) (3.82 to 4.58)
Ortho/EMD/DFDBA 7.29 3.38 3.92 3.42 0.04 3.88
CAL < .0001 .78 < .0001
(n = 24) (1.19) (0.50) (3.47 to 4.37) (0.50) (−0.32 to 0.24) (3.42 to 4.34)
(mm)
Ortho/EMD
7.28 4.00 3.28 4.12 0.12 3.16
(negative control) < .0001 .78 < .0001
(0.68) (0.92) (3.09 to 3.47) (0.88) (−0.32 to 0.24) (2.93 to 3.39)
(n = 25)
Ortho/EMD/FDBA 7.96 3.48 4.48 3.40 −0.18 4.56
< .0001 .75 < .0001
(n = 25) (2.60) (0.87) (3.38 to 5.58) (0.87) (−0.40 to 0.56) (3.45 to 5.43)
Ortho/EMD/DFDBA 7.67 3.34 4.33 3.29 −0.05 4.38
CEJ–BD < .0001 .80 < .0001
(n = 24) (1.90) (0.70) (3.50 to 5.16) (0.64) (−0.33 to 0.43) (3.58 to 5.18)
(mm)
Ortho/EMD
7.44 4.04 3.40 3.92 −0.20 3.52
(negative control) < .0001 .28 < .0001
(0.58) (0.61) (3.06 to 3.74) (0.70) (−0.16 to 0.56) (3.16 to 3.88)
(n = 25)
Ortho/EMD/FDBA 0.17 0.18 −0.01 0.19 −0.01 −0.02
.17 .24 .02
(n = 25) (0.03) (0.03) (−0.03 to 0.004) (0.03) (−0.03 to 0.07) (−0.03 to 0.003)
Ortho/EMD/DFDBA 0.18 0.19 −0.01 0.19 0.0 −0.01
.33 1.00 .33
PI (n = 24) (0.03) (0.04) (−0.03 to 0.01) (0.04) (−0.02 to 0.02) (−0.03 to 0.01)
Ortho/EMD 0.01
0.18 0.19 −0.01 0.18 0.0
(negative control) .17 (−0.02 to .17 1.00
(0.02) (0.03) (−0.03 to 0.01) (0.02) (−0.01 to 0.01)
(n = 25) 0.004)
Ortho/EMD/FDBA 18 13 5.0 13 0.0 5.0
< .0001 1.00 < .0001
(n = 25) (3.3) (2.4) (3.40 to 6.60) (2.2) (−128 to 1.28) (3.45 to 6.55)
Ortho/EMD/DFDBA 19 13 6.0 13 0.0 6.0
< .0001 1.00 < .0001
BOP (%) (n = 24) (3.6) (1.7) (4.41 to 7.59) (1.9) (−1.08 to 1.08) (4.33 to 7.60)
Ortho/EMD
18 12 6.0 12 0.0 6.0
(negative control) < .0001 1.00 < .0001
(2.8) (1.6) (4.74 to 7.26) (1.6) (−0.89 to 0.89) (4.74 to 7.26)
(n = 25)
Ortho/EMD/FDBA 7.96 3.56 4.40
< .0001
(n = 25) (2.59) (0.87) (3.30 to 5.50)
Ortho/EMD/DFDBA 7.63 3.33 4.29
OPAL gain < .0001
(n = 24) (1.92) (0.70) (3.72 to 4.86)
(mm)*
Ortho/EMD
7.36 4.04 3.32
(negative control) < .0001
(0.64) (0.68) (2.94 to 3.70)
(n = 25)
*Comparison at baseline (initial surgery) and 6-month re-entry.

that both FDBA/EMD and DFDBA/EMD are not more Our previous trial showed a difference in only graft
effective than EMD alone when combined with forced material (EMD/FDBA versus EMD/DFDBA),8 whereas the
eruption in soft and hard tissue improvement in current trial compared Ortho/EMD/FDBA-treated sites
infrabony defects, is rejected. to the Ortho/EMD controls and Ortho/EMD/DFDBA-

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Table 3 Results of multiple comparisons of PD, CAL, OPAL, and radiographic bone gain

Ortho/EMD/FDBA vs Ortho/EMD/DFDBA vs Ortho/EMD/FDBA vs

Ortho/EMD (control) Ortho/EMD (control) Ortho/EMD/DFDBA
Comparison Difference (95% CI) P Difference (95% CI) P Difference (95% CI) P
1 year 0.96 (0.51 to 1.40) < .0001 0.85 (0.16 to 1.54) .016 0.11(−0.60 to 0.82) .759
PD reduction
3 years 1.00 (0.55 to 1.45) < .0001 0.89 (0.22 to 1.56) .010 0.11 (−0.59 to 0.81) .760
Primary outcomes
1 year 1.00 (0.61 to 1.40) < .0001 0.64 (0.18 to 1.10) .007 0.36 (−0.19 to 0.91) .200
CAL gain
3 years 1.04 (0.62 to 1.46) < .0001 0.72 (0.23 to 1.21) .004 0.32 (−0.24 to 0.88) .263
Secondary outcome OPAL gain at 6 months 1.08 (0.08 to 2.08) .034 0.97 (0.38 to 1.56) .001 0.11 (−1.02 to 1.24) .848
1 year 1.08 (0.07 to 2.09) .035 0.93 (0.34 to 1.52) .002 0.15 (−0.97 to 1.27) .790
Radiographic bone gain CEJ–BD
3 years 1.04 (0.04 to 2.04) .044 0.86 (0.25 to 1.47) .006 0.18 (−0.94 to 1.30) .750

treated sites to the Ortho/EMD controls. However, the
effectiveness of these interventions should be com-
pared with the current treatment standard or placebo
treatment.15 Open flap debridement (OFD) has a limita-
tion to alter the pre-orthodontic periodontal condition
for advanced interdisciplinary cases. Performing an
Ortho/OFD interventon might cause further breakdown
of periodontal tissue because the functioning PDL
fibers were not obtained by OFD.4,16 In addition, sys-
tematic reviews confirm that the use of EMD for peri-
odontal osseous defects yields significantly higher soft
tissue improvements than OFD alone.17-19 To that end,
we chose to compare Ortho/EMD alone, without graft
materials, as the control, instead of Ortho/OFD in the
current trial.
The PD reduction of 3.4 mm and CAL gain of 3.3 mm
in the Ortho/EMD control-treated site at 1 year post-
surgery in the current trial was comparable to that of
the EMD control-treated site in the previous trial
(3.3 mm and 3.0 mm, respectively).8 These values were
within the ranges of CAL gain of 2.0 mm to 4.5 mm and
PD reduction of 3.0 mm to 5.1 mm in an EMD-treated
site reported by a review paper.20 Unfortunately, the
great heterogeneity among studies makes it impossible
to accurately review orthodontic regenerative combi-
nation therapies.5-7,21 These findings suggest that it is
possible to draw conclusions on the ability of these
graft materials to improve primary and secondary out-
comes compared to the Ortho/EMD control, because
no groups had statistically significant differences in PD
reduction and CAL gain between 1 and 3 years postop-
erative. The positive results observed in the current
patient population might be attributable to the high
level of plaque control and the frequency of profes-
sional maintenance visits. All patients were observed at
least every 6 months over the 3-year period. As a result,
PI and BOP showed no significant differences between
1 year and 3 years postoperative (Table 2). A systematic
review suggested that the key to successful orthodon-
tic regenerative combined therapy is the maintenance
of excellent oral hygiene.7
Furthermore, the groups were strikingly similar after
reviewing baseline data (Table 1); therefore, our ran-
domized design was effective, and should have pre-
vented selection bias. In the current trial, initial defect
depths22 and widths,23 which were associated with CAL
gain in regenerative therapy using EMD, were not mea-
sured. However, randomization provides a powerful
tool for controlling confounding factors that may be
unknown or difficult to measure, and helped to elimi-
nate bias in the current trial.
In light of the factors given above, statistically sig-
nificant differences were found in all subjects between
both interventions and the Ortho/EMD control. More-
over, clinically significant differences were found in PD
reduction (1.0 mm and 1.0 mm) and CAL gain (1.0 mm
and 1.0 mm) at 1 and 3 years postoperative, respect-
ively, and in osseous fill (1.1 mm) at 6 months re-entry
between the Ortho/EMD/FDBA and Ortho/EMD control
sites. Additionally, clinically significant differences were

488 VOLUME 46 • NUMBER 6 • JUNE 2015


observed in osseous fill (1.0 mm) at 6 months re-entry
between the Ortho/EMD/DFDBA and Ortho/EMD con-
trol sites.24-26 Our findings established new clinical prac-
tice guidelines for orthodontic regenerative combina-
tion therapy. The clinical outcomes were obtained
using orthodontic extrusive force/EMD with allograft
materials.
Mechanical stimulation using orthodontic extrusive
force can play a critical role in periodontal soft and hard
tissue development.27 Forced eruption (or orthodontic
extrusion) has capitalized on this principle to treat peri-
odontal complications including 1- or 2-wall infrabony
defects, inadequate biologic width due to subgingival
caries, and root fracture in the region of the alveolar
crest, which cannot be solved by surgery alone, as a
nonsurgical treatment option.28,29 It can also be demon-
strated that the crown-to-root ratio can remain virtually
unchanged or possibly improve compared to conven-
tional surgery.30 Thus the major advantage of forced
eruption is that it is a nonsurgical treatment option for
patients in need of conventional orthodontic therapy.
The only limitation is for a patient with advanced peri-
odontal disease due to lack of intact PDL fibers, as pre-
viously noted. Therefore, an orthodontic regenerative
combined approach could result in an improved prog-
nosis of the tooth.
Comparison with other studies
Our past RCT8 documented that both EMD/FDBA and
EMD/DFDBA interventions resulted in greater soft tis-
sue improvement than with EMD alone at 1 and 3 years
postoperative. Furthermore, clinically significant differ-
ences were found in PD reduction (1.2 mm and 1.3 mm)
and CAL gain (1.1 mm and 1.2 mm) at 1- and 3-year
follow-ups between the EMD/FDBA and EMD control
sites; ie, the EMD/FDBA intervention had better soft tis-
sue improvement than the EMD/DFDBA intervention.
Similar findings in the current trial were also obtained
in PD reduction (1.0 mm and 1.0 mm) and CAL gain
(1.0 mm and 1.0 mm) at 1- and 3-year follow-ups
between the Ortho/EMD/FDBA and Ortho/EMD control
sites. These results are consistent with other studies; for
example, a clinical case series documented that FDBA/
VOLUME 46 • NUMBER 6 • JUNE 2015
Q U I N T E S S E N C E I N T E R N AT I O N A L
Ogihara/Tarnow
EMD had a better CAL gain than DFDBA/EMD at 6
months post-surgery for the treatment of infrabony
defects.31 Rummelhart et al32 reported the response to
treatment, demonstrating that when differences
occurred, the FDBA implant site usually exhibited a bet-
ter response to treatment by CAL gain, PD reduction,
and osseous fill. One possible explanation for the small
differences between the interventions in these cases
could be that the FDBA might be more resistant to
probing due to the residual graft particles and did not
enhance true attachment. More importantly, in both
our current and past trials,8 there were statistically sig-
nificant differences between the interventions and
control group, as well as clinical differences in osseous
fill at 6 months and radiographic bone gain at 1 and 3
years postoperative (Table 3). The probing resistance
from FDBA graft particles did not influence the surgical
hard tissue measurement (OPAL) or the radiographic
hard tissue measurement (radiographic bone gain).
Strengths and limitations of the study
One potential limitation is that stents were not used to
facilitate reproducible measurements. Between the 1-
and 3-year follow-up period, in many cases, the end-
odontically treated teeth were replaced by provisional
restorations and/or final restorations, which made
using stents difficult. Furthermore, the restoration mar-
gins might have been moved to more apical positions
when replacing the old restorations with the new ones.
This influenced the CAL measurements; however, these
problems are unavoidable in long-term observational
studies. Another shortcoming is that the surgical oper-
ator and examiner was the same person (SO) because
the current trial was conducted in a single periodontal
practice, and this limitation should be overcome in
future prospective trials.
Furthermore, minocycline was added to all of the
grafting materials but was not added to the Ortho/EMD
alone group, and this might have influenced the treat-
ment outcomes. A recent study has suggested that
application of locally delivered minocycline with flap
surgery leads to statistically significant PD reduction
and CAL gain compared with flap surgery alone for the
489
Q U I N T E S S E N C E I N T E R N AT I O N A L
Ogihara/Tarnow
treatment of CP at 6 months post-surgery.12 Finally, the
graft material used in this trial did not come from a
single donor. This could have influenced the treatment
outcome as variation in age and sex of the donors may
have impacted the graft’s inductivity.33 However, all
graft materials in the current study were obtained from
the same tissue bank to minimize the effect of different
processing protocols among tissue banks.34
CONCLUSION
This study showed that both forced eruption/EMD/
FDBA and forced eruption/EMD/DFDBA combination
therapies result in greater soft tissue improvements at
1- and 3-year follow-ups in addition to greater hard tis-
sue improvements at 6-months re-entry compared with
forced eruption/EMD alone. Both graft materials were
successful in managing deep infrabony defects when
combined with forced eruption/EMD.
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